In recent years, ischemic cerebrovascular disorders (cerebral infarction, cerebral edema, cerebral hemorrhage, cerebral contusion, neonatal hypoxic-ischemic encephalopathy), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease), lung diseases (pulmonary oxygen intoxication, adult respiratory distress syndrome), ischemic heart diseases (angina, myocardial infarction, etc.), cardiovascular diseases (arteriosclerosis), gastrointestinal diseases (peptic ulcer, ulcerative colitis, Crohn's disease), etc., the conditions and diseases wherein ischemia and an inflammatory substance associated with ischemia is considered to be involved in the onset or worsening thereof are wide-ranging and too numerous to mention. Most of these diseases are progressive, and the development of the preventive agent and therapeutic agent is strongly awaited.
Ischemic cerebrovascular disorders, in particular cerebral infarction, are progressive diseases wherein various mechanisms of disorders take place in a domino fashion, because of a decrease in the cerebral blood flow, and the brain damage spreads from the ischemic core to the periphery. Although the prevention of damage in the acute stage is certainly important, the treatment in the subacute and chronic stages after the onset of the disease is very important in view of the seriousness and QOL. Therapeutic agents usable after the onset of cerebral infarction are very scarce; in particular there are no practical therapeutic drugs for the subacute and chronic stages after the onset of the disease. At present, there are thrombolytic agents such as tissue plasminogen activator (tPA) and hydroxy radical scavengers such as edaravone as the therapeutic drugs for acute stage cerebral infarction to improve the ischemic core due to decreased cerebral blood flow. However, they have problems of serious side effects such as bleeding and renal failure. Thus, the development of an excellent therapeutic drug for the ischemic cerebrovascular disorder in the subacute or chronic stage is expected, which can afford the time up to the start of application after the onset of cerebral infarction.
The inventors have disclosed that, when vitamin E homologs were intravenously administered to the mouse middle cerebral artery (MCA) occlusion model twice, immediately before infarction and during infarction, for prophylactic administration, 2R-γ-tocopherol (γ-Toc) and 2R-α-tocotrienol (α-T3) exhibited an excellent infarct inhibitory effect, and therefore have a preventive effect in vivo on the cerebral infarction damage in the acute stage (Non-patent literature 1).
Vitamin E homologs are each insoluble in water and cannot be administered intravenously so that no rapid bioavailability can be secured. Thus, experiments have been attempted to intravenously administer them by making them soluble with an organic solvent such as dimethyl sulfoxide (DMSO) or a surfactant. However, the solubilization with such an organic solvent is not clinically suitable and the use of a large amount of a nonionic surfactant may cause a serious problem such as anaphylactic shock. The use of them cannot eliminate harmful effects completely when administered repeatedly.
The inventors have disclosed that a specific tocopherol derivative (Non-patent literature 2) and a tocotrienol derivative (patent literature 1) were intravenously administrable water-soluble derivative. The sodium salt of tocopheryl phosphate is also known as a water-soluble derivative of tocopherol.
However, there have been so far no reports regarding the therapeutic effects of vitamin E homologs or the derivatives of vitamin E homologs for ischemia-reperfusion injury by the administration thereof after the infarction (ischemia) reperfusion, i.e., after the onset of infarction, for the therapeutic administration.
In addition, there have been no reports regarding the preventive effect of the derivatives of vitamin E homologs for cerebral infarction injury in the acute stage by intravenous administration thereof both immediately before infarction and during infarction for the prophylactic administration.
On the other hand, farnesol is a kind of sesquiterpene having three isoprene units and it is a colorless liquid contained in the essential oil of rose, lemongrass, and citronella. Farnesol is used as a fragrance and a skin protective agent and is expected to possess excellent pharmaceutical effects such as a preventive effect against hyperlipidemia, an antimicrobial effect against fungi, and a protective effect against oxidative damage.
There have been so far no reports, however, that farnesol and its analogs and their derivatives achieve a therapeutic effect for ischemia-reperfusion injury by the administration thereof after the infarction (ischemia) reperfusion, i.e., after the onset of infarction, for the therapeutic administration. There also have been no reports that they achieve a preventive effect for cerebral infarction injury in the acute stage by intravenous administration thereof both immediately before infarction and during infarction for the prophylactic administration.
In addition, farnesol is a totally water-insoluble and volatile compound. Therefore, the solubilization method by the addition of a large amount of nonionic surfactant is investigated for the preparation of a water-soluble drug or water-based cosmetics of farnesol. The use of a large amount of surfactant may cause a serious problem such as anaphylactic shock.
Thus, a farnesol derivative which has a high melting point, is solid at room temperature, has a high water-solubility, and is capable to provide a useful in vivo action has also been in demand.    PATENT LITERATURE 1: Japanese Patent Application No. 2000-268885    NON-PATENT LITERATURE 1: Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M. Vitamin E isoforms α-tocotrienol and γ-tocopherol prevent cerebral infarction in mice. Neuroscience Let 2003; 337:56-60.    NON-PATENT LITERATURE 2: Takata J., Hidaka R., Yamasaki A., Hattori A., Fukushima T., Tanabe M., Matsunaga K., Karube Y., Imai K., Novel d-γ-tocopherol derivative as a prodrug for d-γ-tocopherol and a two-step prodrug for S-γ-CEHC. J. Lipid Res., 43, 2196-2204 (2002).